Peripheral BDZ Receptor - Biomarker of Neurotoxicity

外周 BDZ 受体 - 神经毒性生物标志物

基本信息

批准号：
10176485
负责人：
Tomas R Guilarte
金额：
$ 46.26万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176485
关键词：
Acute Animals Appearance Astrocytes Attention Basic Science Behavior Behavioral Benzodiazepine Receptor Biological Markers Brain Brain Diseases Brain Injuries Catalytic Domain Cell membrane Cell surface Cellular biology Chemicals Clinical Clinical Research Cytokine Gene Disease Progression Encephalitis Endoplasmic Reticulum Environmental Health Enzymes Equilibrium Exposure to Female Flow Cytometry Gene Deletion Gene Expression Gene Proteins Glutathione Goals Health Heme Homeostasis Human Image Injury Knock-out Knockout Mice Knowledge Laboratories Ligands Lipopolysaccharides Measures Mediating Membrane Microglia Mitochondria Molecular Movement Mus NADPH Oxidase Names National Institute of Environmental Health Sciences Nerve Degeneration Nervous System Physiology Neuroglia Neurologic Neurologic Effect Oxidation-Reduction Oxidative Stress Pathway interactions Peripheral Phagocytosis Pharmacology Physiologic pulse Physiology Play Positron-Emission Tomography Production Proteins Psyche structure Reactive Nitrogen Species Reactive Oxygen Species Recovery Research Role Steroid biosynthesis Strategic Planning Study Section Techniques Therapeutic Validation Wild Type Mouse base biological adaptation to stress biological research cell motility cell type clinical biomarkers cytochrome b558 dimer effectiveness evaluation environmental chemical imaging study improved insight interest male neuroimaging marker neuroinflammation neuropathology neurotoxic neurotoxicity novel novel therapeutic intervention pre-clinical preclinical study protein expression protein protein interaction receptor response sex tert-Butylhydroperoxide therapeutic effectiveness virtual

项目摘要

Project Summary (Abstract): The long-term goal of this research is to understand the function(s) of Translocator Protein 18 kDa (TSPO) in glial cells, specifically in microglia. TSPO is a glial stress response protein that we have previously validated as a biomarker of brain injury and inflammation and it is currently used in preclinical and clinical Positron Emission Tomography (PET) imaging studies throughout the world. TSPO is a sensitive biomarker that is able to detect brain injury and neuroinflammation in a number of human neurodegenerative and mental conditions as well as in neurodegeneration induced by exposures to environmental chemicals. Furthermore, we are currently using TSPO as a biomarker of neurotoxicity to screen the neurotoxicity of chemicals for which there is currently no information on their potential to damage the brain. Despite the widespread use of TSPO in clinical and preclinical studies, there is a paucity of knowledge on the function(s) of TSPO in glial cells (microglia and astrocytes), the cell types that upregulate TSPO under neuropathological conditions. This proposal is aimed at understanding a novel interaction that we have discovered between TSPO and NADPH Oxidase (NOX2) in microglia that may provide important insights on modulation of brain reactive oxygen species (ROS) production and neuroinflammation. We present rigorously performed studies demonstrating the TSPO-NOX2 interaction and its modulation by microglia activation. There are three specific aims in the proposed research. Specific aim 1 will examine the function of TSPO in primary microglia generated from wildtype and global TSPO knockout (TSPO-gKO) as well as microglia-specific conditional TSPO (mTSPO-cKO) mice. Specific aim 2 will examine the subcellular localization and functional significance of the TSPO-NOX2 interaction in microglia. Finally, specific aim 3 will examine the neurological effects of TSPO deletion (global and microglia-specific) at the whole animal level. Combined, the proposed studies will generate new information on the function of TSPO in microglia. We will use state-of-the-art molecular and cellular techniques to understand the function of TSPO in microglia. A precise understanding of this novel TSPO-NOX2 interaction will provide new insights for devising therapeutics strategies for neurodegenerative conditions that involve neuroinflammation since NOX2 is involved in microglia-mediated neurodegeneration. This research topic is consistent with strategic objective 1 in advancing environmental health sciences basic biological research which is an integral part of the National Institute of Environmental Health Sciences strategic plan 2018-2023: Advancing Environmental Health Science, Improving Health 2.0.

项目摘要（摘要）：这项研究的长期目标是了解神经胶质细胞（特别是小胶质细胞）中的易位蛋白 18 kDa (TSPO)。 TSPO 是神经胶质应激反应我们之前已经验证过这种蛋白质是脑损伤和炎症的生物标志物，目前它正在用于世界各地的临床前和临床正电子发射断层扫描 (PET) 成像研究。 TSPO 是一种敏感的生物标志物，能够检测多种人类的脑损伤和神经炎症。神经退行性疾病和精神疾病以及因暴露于环境而引起的神经退行性变环境化学品。此外，我们目前正在使用 TSPO 作为神经毒性的生物标志物来筛选化学物质的神经毒性，目前尚无关于其可能损害大脑的信息。尽管 TSPO 在临床和临床前研究中得到广泛使用，但人们对 TSPO 的了解还很缺乏。 TSPO 在神经胶质细胞（小胶质细胞和星形胶质细胞）中的功能，这些细胞类型在以下情况下上调 TSPO：神经病理学状况。该提案旨在理解我们所拥有的一种新颖的互动在小胶质细胞中发现 TSPO 和 NADPH 氧化酶 (NOX2) 之间的关系，这可能提供重要的见解调节大脑活性氧（ROS）的产生和神经炎症。我们严谨呈现进行的研究证明了 TSPO-NOX2 相互作用及其通过小胶质细胞激活的调节。那里是拟议研究的三个具体目标。具体目标 1 将检查 TSPO 在初级中的功能由野生型和全局 TSPO 敲除 (TSPO-gKO) 以及小胶质细胞特异性产生的小胶质细胞条件 TSPO (mTSPO-cKO) 小鼠。具体目标 2 将检查亚细胞定位和功能小胶质细胞中 TSPO-NOX2 相互作用的重要性。最后，具体目标 3 将检查神经系统 TSPO 缺失（全局和小胶质细胞特异性）在整个动物水平上的影响。综合起来，建议研究将产生关于小胶质细胞中 TSPO 功能的新信息。我们将使用最先进的分子和细胞技术来了解 TSPO 在小胶质细胞中的功能。准确的理解这种新颖的 TSPO-NOX2 相互作用将为设计治疗策略提供新的见解由于 NOX2 参与小胶质细胞介导的神经退行性疾病，因此涉及神经炎症神经变性。本研究课题与促进环境发展的战略目标1一致健康科学基础生物学研究，是国家环境研究所的组成部分健康科学战略计划 2018-2023：推进环境健康科学，改善健康 2.0。